Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act

MacGregor, Paula; Szöőr, Balázs; Savill, Nicholas J.; Matthews, Keith R.

doi:10.1038/nrmicro2779

Cited by 108 publications

(113 citation statements)

References 83 publications

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“…In many cases, antigens appearing very progressively do not represent a strong modification and hence are not eliminated 43,44 . Motifs changing at a very high rate can make protective immune responses impossible, as happens with many parasites and viruses including HIV 45,46,47 . Indeed, in these conditions, the time required for the generation of protective immune response is greater than the time needed for the pathogens to mutate.…”

Section: A Response Based On the Variation Of The Quantities Of Antigmentioning

confidence: 99%

The speed of change: towards a discontinuity theory of immunity?

Pradeu¹,

2013

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(E.V.). PrefaceImmunology, though deeply experimental in everyday practice, is also a theoretical discipline.Recent advances in the understanding of innate immunity, how it is triggered, and how it shares features previously uniquely ascribed to the adaptive immune system, can contribute to the refinement of immunology's theoretical framework. In particular, natural killer (NK) cells 2 and macrophages are activated by transient modifications, but adapt to long-lasting modifications that occur in the surrounding tissue environment. This process allows the maintenance of self-tolerance while permitting efficient immune responses. Extending this idea to other components of the immune system, we propose here some general principles that lay the ground for a unifying account of immunity, the discontinuity theory. According to this theoretical framework, effector immune responses (i.e., activated responses that lead to the potential elimination of the target antigen) are triggered by an antigenic discontinuity, that is, by the sudden modification of molecular motifs with which immune cells interact.

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Section: A Response Based On the Variation Of The Quantities Of Antigmentioning

confidence: 99%

The speed of change: towards a discontinuity theory of immunity?

Pradeu¹,

2013

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“…Transmission typically occurs through the saliva of blood-sucking insect vectors during feeding. The life cycle of African trypanosomes, such as Trypanosoma congolense, T. brucei brucei, T. b. gambiense, and T. b. rhodesiense, is fully dependent on cyclical development in the tsetse fly vector and highly complex (1). Thus, these parasites are restricted to areas inhabited by the tsetse fly (i.e., sub-Saharan Africa).…”

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confidence: 99%

Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes

Dean

Gould

Dewar

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

121

219

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Viability of the tsetse fly-transmitted African trypanosome Trypanosoma brucei depends on maintenance and expression of its kinetoplast (kDNA), the mitochondrial genome of this parasite and a putative target for veterinary and human antitrypanosomatid drugs. However, the closely related animal pathogens T. evansi and T. equiperdum are transmitted independently of tsetse flies and survive without a functional kinetoplast for reasons that have remained unclear. Here, we provide definitive evidence that single amino acid changes in the nuclearly encoded F 1 F O -ATPase subunit γ can compensate for complete physical loss of kDNA in these parasites. Our results provide insight into the molecular mechanism of compensation for kDNA loss by showing F O -independent generation of the mitochondrial membrane potential with increased dependence on the ADP/ATP carrier. Our findings also suggest that, in the pathogenic bloodstream stage of T. brucei, the huge and energetically demanding apparatus required for kDNA maintenance and expression serves the production of a single F 1 F O -ATPase subunit. These results have important implications for drug discovery and our understanding of the evolution of these parasites.dourine | surra | dyskinetoplastic | RNA editing | mitochondrial DNA

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“…The work further suggested that the early period of infection, when long slender forms predominate, is where most of the population will be able to switch VSGs, and the authors suggest that this is a period of initial adaptation to the new environment enabling the trypanosome to overcome, for example, antibodies present due to previous infections or coinfections. After this period of putative rapid switching and adaptation, short stumpy forms predominate and only a minority of the population are able to switch to a new variant for the remainder of the infection timescale (230). These observations emphasize the requirement for further analysis of the chronic stages of infection, and in particular how the observation that only a small proportion of trypanosomes are switching VSGs may potentially influence the mechanistic processes during infection.…”

Section: The Interplay Between Differentiation and Vsg Switchingmentioning

confidence: 87%

DNA Recombination Strategies During Antigenic Variation in the African Trypanosome

2015

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Survival of the African trypanosome in its mammalian hosts has led to the evolution of antigenic variation, a process for evasion of adaptive immunity that has independently evolved in many other viral, bacterial and eukaryotic pathogens. The essential features of trypanosome antigenic variation have been understood for many years and comprise a dense, protective Variant Surface Glycoprotein (VSG) coat, which can be changed by recombination-based and transcription-based processes that focus on telomeric VSG gene transcription sites. However, it is only recently that the scale of this process has been truly appreciated. Genome sequencing of Trypanosoma brucei has revealed a massive archive of >1000 VSG genes, the huge majority of which are functionally impaired but are used to generate far greater numbers of VSG coats through segmental gene conversion. This chapter will discuss the implications of such VSG diversity for immune evasion by antigenic variation, and will consider how this expressed diversity can arise, drawing on a growing body of work that has begun to examine the proteins and sequences through which VSG switching is catalyzed. Most studies of trypanosome antigenic variation have focused on T. brucei , the causative agent of human sleeping sickness. Other work has begun to look at antigenic variation in animal-infective trypanosomes, and we will compare the findings that are emerging, as well as consider how antigenic variation relates to the dynamics of host–trypanosome interaction.

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Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act

Cited by 108 publications

References 83 publications

The speed of change: towards a discontinuity theory of immunity?

The speed of change: towards a discontinuity theory of immunity?

Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes

DNA Recombination Strategies During Antigenic Variation in the African Trypanosome

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